Medication-related osteonecrosis of the jaw

Medication-related osteonecrosis of the jaw (MRONJ) is an adverse drug reaction characterized by progressive, non-healing destruction of maxillary or mandibular bone in patients exposed to antiresorptive and/or antiangiogenic therapy, in the absence of prior jaw irradiation or metastatic jaw disease.[1] It is essentially confined to the tooth-bearing jaws, a tropism attributed to their high remodeling rate, thin overlying mucosa, and constant exposure to the oral microbial environment.[1] Most lesions arise in the posterior mandible and are precipitated by a dentoalveolar insult—most often tooth extraction or periapical/periodontal infection—that fails to heal.[3]

Pathogenesis is multifactorial and incompletely resolved, with converging contributions from osteoclast suppression and impaired bone turnover, inhibited angiogenesis, local infection/inflammation, and immune dysfunction.[1][4][5] The signature imaging theme is a mixed sclerotic–lytic lesion with sequestration and periosteal new bone, and management is stage-driven, ranging from conservative infection and pain control to surgical resection.[6][7]

The term medication-related osteonecrosis of the jaw was adopted by the American Association of Oral and Maxillofacial Surgeons (AAOMS) in 2014, replacing the earlier bisphosphonate-related osteonecrosis of the jaw (BRONJ) once denosumab and antiangiogenic agents were recognized as causes.[8][9] Antiresorptive-related osteonecrosis of the jaw (ARONJ) is a near-synonym used when only bisphosphonates and RANKL inhibitors are implicated, and remains the preferred term in some national guidelines.[10] The umbrella term osteonecrosis of the jaw (ONJ) encompasses MRONJ, osteoradionecrosis, and other etiologies.[10]

The AAOMS case definition requires all three of: current or prior antiresorptive therapy (alone or with immune modulators or antiangiogenic agents); exposed bone, or bone probed through an intraoral or extraoral fistula, persisting more than 8 weeks; and no history of jaw radiation or metastatic jaw disease.[7][32] Staging spans at-risk, Stage 0 (no exposed bone; nonspecific symptoms and/or radiographic change), Stage 1 (asymptomatic exposed/probeable bone), Stage 2 (exposed bone with infection), and Stage 3 (infection plus pathologic fracture, extraoral fistula, oroantral/oronasal communication, or osteolysis reaching the inferior border or sinus floor).[1][12][32] Stage 0 is contentious: the International Task Force cautions it may overdiagnose MRONJ, since symptoms often reflect ordinary periapical or periodontal disease.[7]

MRONJ risk is dominated by drug, dose, and cumulative exposure. Among osteoporosis patients on low-dose therapy, incidence is low—roughly 0.01–0.05% with oral bisphosphonates and 0.04–0.3% with denosumab—whereas cancer patients on high-dose regimens reach 0.7–5.4%, and up to about 13% in some metastatic breast cancer or sequential-therapy cohorts.[4][32] Risk is approximately 100-fold higher in the oncologic than the osteoporotic setting.[13]

Denosumab carries a higher risk than bisphosphonate monotherapy, and sequential bisphosphonate-then-denosumab exposure is intermediate to high; risk rises steeply after roughly 40 months of use.[4][14] Established cofactors include dentoalveolar surgery and oral infection (the dominant local triggers, present in most cases), corticosteroid and antiangiogenic/chemotherapy co-administration, diabetes, smoking, and older age.[4] Patients are predominantly older adults and, in osteoporosis cohorts, overwhelmingly women.[14] The mandible is affected more often than the maxilla, with most lesions in posterior, tooth-bearing segments.[15]

The hallmark is exposed, non-healing necrotic bone or a mucosal/cutaneous fistula that probes to bone, persisting beyond 8 weeks.[16] However, a substantial minority present as non-exposed (Stage 0) disease with nonspecific findings only.[8][12]

• Common symptoms and signs: jaw pain of bony origin, soft-tissue swelling, mucosal inflammation, a non-healing extraction socket, intraoral or cutaneous fistula, purulent discharge, halitosis, and sudden tooth or implant mobility. Pain is the most frequently reported symptom but is often absent at onset.[6][16]
• Occasional/advanced features:lower-lip numbness (Vincent's symptom/numb chin) from inferior alveolar nerve involvement, trismus, mandibular deformation, pathologic fracture, and oroantral/oronasal communication with sinonasal symptoms.[8][16]
• Tempo: typically indolent and progressive, punctuated by episodes of acute infection; a dentoalveolar procedure or local infection commonly precedes onset.[3]
• Red flags prompting urgent evaluation: pathologic fracture or extraoral fistula (Stage 3 features), rapidly expanding infection, and new neurosensory deficit.[1][12]

In cancer patients, a key diagnostic red flag is that overlapping clinical and imaging features may instead represent jawbone metastasis, which must be actively excluded.[17]

Imaging is not required to diagnose overt MRONJ but is central to defining lesion extent, planning surgery, and following disease, and the true extent of bone involvement is consistently larger than the clinically visible exposure.[17] No finding is pathognomonic; diagnosis rests on integrating imaging with drug history and examination.[7][16] Plain films (periapical and panoramic) reliably depict sclerosis and lytic change but are insensitive for periosteal reaction, cortical perforation, and sequestration, which are far better resolved on volumetric sections.[11][16]

Location and distribution

Lesions center on the alveolar process of the tooth-bearing jaws, most often the posterior mandible, frequently at or adjacent to an extraction site or a tooth with periapical/periodontal disease.[17] Multifocal and bilateral involvement can occur, particularly with high-dose therapy.[15]

Periphery and shape

The periphery is characteristically ill-defined, with a poorly demarcated transition between abnormal and normal bone and no corticated margin—reflecting an admixture of reactive sclerosis and destructive change rather than an expansile, encapsulated process.[15][17]

Internal architecture

The internal pattern is typically mixed sclerotic and lytic:[15][18]

• Osteosclerosis is the earliest and most frequent finding—regional or diffuse increased density with trabecular disorganization and poor corticomedullary differentiation; it is often most prominent in the alveolar process and may extend beyond a sequestrum. In early/Stage 0 disease, focal alveolar osteosclerosis, altered trabecular pattern, and lamina dura thickening may be the only signs.[6][15][16][17]
• Osteolysis represents progressive necrosis and secondary infection and tends to appear with more advanced disease.[15][19]
• Mixed-type osteosclerosis describes dense sclerotic bone containing multiple small hypodense foci.[19]
• Sequestrum formation—necrotic bone demarcated by a radiolucent resorptive margin—is a hallmark of established disease, present in roughly one-third to two-thirds of cases depending on cohort and modality. Sequestra may be trabecular, cortical, or mixed, with mixed and larger sequestra favoring high-dose oncologic disease.[11][13][19]

Effects on teeth and adjacent structures

• Persistent/non-healing extraction socket with unresorbed lamina dura or a "socket sclerosis" pattern.[6][17]
• Widened periodontal ligament space and thickened lamina dura as early periodontal-region changes.[6][16]
• Thickening of the inferior alveolar canal walls and a prominent/altered mandibular canal; in the maxilla, maxillary sinus floor thickening, mucosal thickening, or opacification.[17]

Cortical involvement, periosteal reaction, and extent

Cortical erosion and perforation of the buccal or lingual plate occur as disease advances.[11][16] Periosteal new bone (solid, laminated/onion-skin, or irregular) is more frequent in MRONJ than in osteoradionecrosis and, when present, is an adverse prognostic sign.[17][18][19] Extension to the inferior mandibular border or sinus/nasal floor, and pathologic fracture, define the most advanced (Stage 3) involvement.[8][12]

Variants

• Non-osteolytic MRONJ: minimal or absent lysis despite extensive marrow necrosis, more common with high-dose denosumab and associated with poorer outcome.[19][20]
• Periosteal-reaction–dominant type: prominent periosteal response with little osteolysis.[19]
• "Bone-within-bone" appearance: an expansile lytic lesion containing a dense central sequestrum; rare but linked to prolonged course and poor prognosis.[19]

Maxilla versus mandible

Radiographic expression is jaw-specific. Mandibular lesions more often show sequestration, periosteal new bone, and sclerosis, whereas maxillary lesions are dominated by osteolysis and may otherwise appear subtle—so isolated maxillary osteolysis in an at-risk patient should itself raise suspicion.[15] Maxillary disease additionally threatens the sinus and nasal floor.[17]

Advanced cross-sectional imaging adds value chiefly for early, non-exposed disease and for excluding malignancy.

Marrow and soft-tissue assessment

MRI is the most sensitive technique for early marrow change, showing bone marrow edema (low T1, high T2) before cortical destruction, making it useful in non-osteolytic cases; the necrotic core is typically low signal on both T1 and T2, with an enhancing inflammatory rim and adjacent soft-tissue inflammation.[15][17] It also depicts soft-tissue swelling, sinus involvement, air–fluid levels, and fistulae.[17]

Distinguishing osteonecrosis from metastasis

Conventional bone scintigraphy, SPECT, and FDG-PET show increased uptake in both MRONJ and metastasis and cannot reliably separate them.[17] PSMA-PET is more specific for tumor than for inflammation and can help differentiate jaw metastasis (high avidity) from MRONJ (usually low uptake), particularly in prostate and some other solid cancers.[17][21]

MRONJ overlaps clinically and radiographically with other destructive jaw processes; the drug history and the explicit exclusion of radiation and metastasis anchor the diagnosis, but each alternative below requires active consideration before committing to management.

The highest-risk pitfall is mistaking jawbone metastasis for MRONJ in an oncology patient, which can delay cancer-directed therapy; conversely, overcalling Stage 0 from nonspecific radiographic change risks inappropriate discontinuation of bone-protective therapy.[7][17] Because no single microscopic or imaging feature is diagnostic, suspected malignancy warrants biopsy—undertaken cautiously, with oncology input, given the small risk of provoking or worsening MRONJ—supplemented by PSMA-PET where available.[17][21]

MRONJ shows necrotic bone with empty osteocyte lacunae and empty Haversian and Volkmann canals, variable acute and chronic inflammation, and surface bacterial colonization.[22][24] Actinomyces colonies—filamentous "sulphur granules"—are a characteristic and, with targeted special stains (Gram, PAS, Grocott methenamine silver), near-ubiquitous finding, underscoring the infective contribution and the value of requesting these stains.[24][25]

A classic blinded comparison distinguishes the three major osteonecroses mechanistically: MRONJ shows an empty marrow space with empty Howship lacunae, absent/dysfunctional osteoclasts, but viable periosteum; suppurative osteomyelitis shows intense marrow inflammation and vascular thrombosis with retained viable osteoclasts; and osteoradionecrosis shows a hypocellular, hypovascular marrow with nonviable periosteum.[22] In practice, however, these entities cannot be reliably separated by microscopy alone, and histology serves to support—not replace—clinical and imaging diagnosis.[26]

Variant-level findings refine the picture: compared with denosumab-related necrosis, bisphosphonate-related disease shows more RANKL- and TRAP-positive osteoclasts, while denosumab and combined exposure show fewer osteocytes.[27] Paradoxically, some surviving osteoclasts in MRONJ are large, hypernucleated, and detached from bone, consistent with dysfunctional rather than simply reduced resorption.[24][28] Collectively the features point to oversuppressed turnover, disturbed osteocyte networks, and superimposed infection rather than a purely avascular process.[27]

Management is stage-adapted and best delivered through coordinated oncology–dental care, with prevention (pre-therapy dental clearance, elimination of foci of infection, and avoidance of elective dentoalveolar surgery during therapy) remaining the most effective strategy.[7][12]

• At-risk / Stage 0: education, modifiable-risk-factor reduction, symptomatic care, and close dental follow-up.[7]
• Stage 1: antibacterial mouth rinse (e.g., chlorhexidine) and surveillance.[7] Operative therapy (debridement or resection) is an acceptable option at any stage per AAOMS 2022.[32]
• Stage 2: oral antibiotics directed at the polymicrobial flora (e.g., amoxicillin–clavulanate, metronidazole, or clindamycin), pain control, antiseptic rinses, and debridement/removal of mobile sequestra. Intravenous antibiotics are reserved for refractory infection.[7][30]
• Stage 3 / refractory disease: surgical resection (marginal or segmental) with soft-tissue closure, often with reconstruction; mobile sequestra should be removed at any stage, and symptomatic teeth within necrotic bone extracted.[7][12]

Hyperbaric oxygen and ozone therapy are not recommended given insufficient evidence; teriparatide, pentoxifylline–tocopherol, and laser/platelet-derived adjuncts remain investigational.[1][30] Discontinuing the antiresorptive agent ("drug holiday") is adjunctive only—it may aid healing but risks skeletal-related events and fracture, and must be an oncology-led decision.[31]